This application is 371 of PCT/JP00/05453 Aug. 14, 2000.
This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
Some heterocyclic compounds have been known as described, for example, in WO95117393, WO95124393, WO97/03973, U.S. Pat. No. 5,362,879 and EP-A-434034.
This invention relates to new heterocyclic compounds. More particularly, this invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which have prostaglandin I2 (hereinafter referred as PGI2) agonistic activity and pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like, to processes for their production, to a pharmaceutical composition containing the same and to a use thereof for manufacture of medicaments.
Accordingly, one object of this invention is to provide new and useful heterocyclic compounds and pharmaceutically acceptable salts thereof.
Another object of this invention is to provide processes for production of the heterocyclic compounds and salts thereof.
A further object of this invention is to provide a pharmaceutical composition containing, as an active ingredient, said heterocyclic compounds or pharmaceutically acceptable salts thereof.
Still further object of this invention is to provide use of the heterocyclic compounds and pharmaceutically acceptable salts thereof for manufacture of medicaments for the therapeutic and/or prophylactic treatment of arterial obstruction, cerebrovascular disease, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis after percutaneous transluminal coronary angioplasty, hypertension, dermatitis or the like.
The heterocyclic compounds of this invention can be represented by the following formula (I): 
wherein R1 is carboxy or protected carboxy,
R2 is aryl which may have substituent(s),
R3 is aryl which may have substituent(s),
X is oxygen or a pair of hydrogen and R5 (wherein R5 is hydroxy or protected hydroxy), and
A1 and A2 are each independently lower alkylene and prodrug thereof, and its salt.
According to the present invention, the new heterocyclic compounds (I) can be prepared by the processes which are illustrated in the following scheme. 
wherein R1, R2, R3, X, A1 and A2 are each as defined above,
Y is leaving group,
R1a is protected carboxy, and
R1b is carboxy.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,Nxe2x80x2-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), and the like.
The xe2x80x9cprodrugxe2x80x9d means the derivatives of compounds of the present invention having a chemically or metabolically degradable group, which becomes pharmaceutically active after biotransformation.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term xe2x80x9clowerxe2x80x9d is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable xe2x80x9carylxe2x80x9d may include phenyl, naphthyl and the like.
Suitable xe2x80x9clower alkylenexe2x80x9d may include straight one having 1 to 6 carbon atom(s), such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, preferably one having 1 to 3 carbon atom(s).
Suitable xe2x80x9cprotected carboxyxe2x80x9d may include esterified carboxy and the like. Suitable example of the ester moiety of an esterified carboxy may be the ones such as lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.) which may have at least one substituent(s), for example, lower alkanoyloxy(lower)alkyl [e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl, hexanoyloxymethyl, 1(or 2)-acetoxyethyl, 1(or 2 or 3)-acetoxypropyl, 1(or 2 or 3 or 4)-acetoxybutyl, 1(or 2)-propionyloxyethyl, 1(or 2 or 3)-propionyloxypropyl, 1(or 2)-butyryloxyethyl, 1(or 2)-isobutyryloxyethyl, (1 or 2)-pivaloyloxyethyl, 1(or 2)-hexanoyloxyethyl, isobutyryloxymethyl, 2-ethylbutyryloxymethyl, 3,3-dimethylbutyryloxymethyl, 1(or 2)-pentanoyloxyetbyl, etc.], lower alkylsulfonyl(lower)alkyl (e.g. 2-mesylethyl, etc.), mono(or di or tri)-halo(lower)alkyl (e.g. 2-iodoethyl, 2,2,2-trichloroethyl, etc.), lower alkoxycarbonyloxy(lower)alkyl (e.g. methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 2-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, etc.), phthalidylidene(lower)alkyl or (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl [e.g. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl, etc.]; lower alkenyl (e.g. vinyl, allyl, etc.); lower alkynyl (e.g. ethynyl, propynyl, etc.); ar(lower)alkyl which may have at least one substituent(s) such as mono(or di or tri)phenyl(lower)alkyl which may have at least one substituent(s) (e.g. benzyl, 4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, benzhydryl, bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl, 4-hydroxy-3,5-di-tert-butylbenzyl, etc.); aryl which may have at least one substituent(s) (e.g. phenyl 4-chlorophenyl, tolyl, tert-butylphenyl, xylyl, mesityl , cumenyl, etc.); phthalidyl; and the like.
Suitable xe2x80x9csubstituentxe2x80x9d in the term xe2x80x9caryl which may have substituent(s)xe2x80x9d may include halogen, amino, hydroxy, lower alkoxy, lower alkyl as exemplified above, and the like.
Suitable xe2x80x9chalogenxe2x80x9d may include fluoro, chloro, bromo and iodo.
Suitable xe2x80x9clower alkylxe2x80x9d may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like, preferably one having 1 to 4 carbon atom(s).
Suitable xe2x80x9clower alkoxyxe2x80x9d may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable xe2x80x9cacylxe2x80x9d may include (1) lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl, etc.); (2) lower alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.); (3) arenesulfonyl (e.g. benzenesulfonyl, tosyl, etc.); (4) aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, indancarbonyl, etc.); (5) ar(lower)alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.); and the like.
Suitable xe2x80x9cprotected hydroxyxe2x80x9d may include lower alkoxy as exemplified above, acyloxy, siloxy which may have one to three substituent(s), and the like.
Suitable xe2x80x9csubstituentxe2x80x9d in the term xe2x80x9csiloxy which may have one to three substituent(s)xe2x80x9d may include lower alkyl as exemplified above, aryl as exemplified above, and the like.
Suitable xe2x80x9csubstituentxe2x80x9d in the term xe2x80x9clower alkylene which may have substituent(s)xe2x80x9d may include lower alkyl as exemplified above, hydroxy(lower)alkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, etc.) and the like.
Suitable xe2x80x9cleaving groupxe2x80x9d may include halogen as exemplified above, acyloxy (e.g. acetyloxy, methanesulfonyloxy), and the like.
Preferred embodiments of the object compound (I) are as follows:
R1 is carboxy or protected carboxy (more preferably esterified carboxy, most preferably lower alkoxycarbonyl),
R2 is aryl which may have lower alkyl (more preferably phenyl or lower alkylphenyl, most preferably phenyl),
R3 is aryl which may have lower alkyl (more preferably phenyl or lower alkylphenyl, most preferably phenyl),
X is oxygen or a pair of hydrogen and R5 (wherein R5 is hydroxy or protected hydroxy, more preferably R5 is lower alkoxy, most preferable R5 is methoxy), and
A1 and A2 are each independently lower alkylene (more preferably C1-C4 alkylene, most preferably methylene),
Another preferred embodiments of the object compound (I) are as follows: 
wherein
R1 is carboxy or lower alkoxycarbonyl (more preferably ethoxycarbonyl),
R2 is phenyl or lower alkylphenyl, more preferably phenyl,
R3 is phenyl or lower alkylphenyl, more preferably phenyl,
X is oxygen or a pair of hydrogen and R5 (wherein R5 is hydroxy or lower alkoxy), more preferably a pair of hydrogen and lower alkoxy, most preferably a pair of hydrogen and methoxy, and
A1 and A2 are each independently lower alkylene (more preferably methylene).
It is to be noted the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.
It is further to be noted isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.
It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.
Also included in the scope of invention are radiorabelled derivatives of the compound of the formula (I) which are suitable for biological studies.
The processes for preparing the object and starting compounds of the present invention are explained in detail in the following.
The compound (I) or its salt can be prepared by reacting the compound (II) or its salt with the compound (III) or its salt.
This reaction is usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or any other solvent which does not adversely affect the reaction.
The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
The reaction is usually carried out in the presence of a base. Suitable base may include the inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.) or the like, and the organic base such as tri(lower)alkylamino (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), di(lower)alkylaniline (e.g. dimethylaniline, etc.), pyridine or the like.
The compound (I-2) or its salt can be prepared by subjecting the compound (I-1) or its salt to elimination reaction of the carboxy protective group. Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.
(i) For Hydrolysis:
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. The elimination using Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
The reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, 1,2-dimethoxyethane, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
(ii) For Reduction:
Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullman copper, etc.) and the like. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
The object compound (I) of this invention and pharmaceutically acceptable salt thereof have pharmacological activities such as an inhibitory activity on platelet aggregation, vasodilating activity, antihypertensive activity or the like and are prostaglandin I2 agonists, and therefore can be used for treating and/or preventing thrombosis, arterial obstruction (e.g., chronic arterial obstruction, etc.), cerebrovascular disease, gastric ulcer, hepatitis, hepatic insufficiency, hepatic cirrhosis, arteriosclerosis, ischemic heart disease, restenosis or ischemic complications after coronary angioplasty (e.g., PTCA, coronary stenting, etc.), hypertension, inflammation, autoimmune disease, heart failure, renal disease (e.g., renal failure, nephritis, etc.), diabetic complication (e.g., diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, etc.), peripheral circulatory disturbance, dermatitis, chilblain, baldness, bedsore, and the like, inflammatory bowel disease {such as specific inflammatory bowel disease [e.g., infectious enteritis, drug induced colitis (e.g., antibiotics associated colitis, etc), ischemic colitis, etc.], idiopathic inflammatory bowel disease (e.g., ulcerative colitis, Crohn""s disease, etc) and the like }, and the like, and can be also used for protecting organs after transplantation or surgery.
Further, the object compound (I) and pharmaceutically acceptable salt thereof can be also used as a component for organ preserving fluids and as an agent for inhibiting metastasis of cancer.
The object compound (I) was confirmed to have a potent PGI2 agonistic activity. Further in order to show the inhibitory activity on platelet aggregation, pharmacological data of the representative compounds thereof are shown in the following.
[I] Test Compound:
(1) Sodium 3-{[(2R, 4R)-2-(4,5-dipbenyloxazol-2-yl)-4-methoxypyrrolidin-1-yl]methyl}phenoxyacetate
(2) Sodium 3-{[(2R, 4S)-2-(4,5-diphenyloxazol-2-yl)-4-methoxypyrrolidin-1-yl]methyl}phenoxyacetate
[II] Test Method:
Human blood was obtained from healthy volunteers and mixed with 1/10 volume of 3.8% sodium citrate, pH 7.4. The citrate blood was centrifuged at 150xc3x97g for 10 minutes and the platelet rich plasma (PRP) was removed. The remaining blood was centrifuged for a further 10 minutes at 1500xc3x97g to prepare the platelet poor plasma (PPP), which was used as a reference for platelet aggregation. Aggregation studies were carried out using HEMATRACER 801 (NBS, Japan), a 8 channel aggregometer. The test compound solution (25 xcexcl) and the PRP (225 xcexcl) were mixed and stirred at 1000 rpm at 37xc2x0 C. for 2 minutes. Aggregation was induced by ADP solution at the final concentration of 2.5 xcexcM.
[III] Test Result:
The active ingredient of this invention can be used in a form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains a compound (I), as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral, intravenous, intramuscular, parenteral or intramucous applications. The active ingredient may be compounded, for example, with the conventional non-toxic, pharmaceutically acceptable carriers for ointment, cream, plaster, tablets, pellets, capsules, suppositories, solution (saline, for example), emulsion, suspension (olive oil, for example), aerosols, pills, powders, syrups, injections, troches, cataplasms, aromatic waters, lotions, buccal tablets, sublingual tablets, nasal drops and any other form suitable for use. The carriers which can be used are water, wax, glucose, lactose, gum acacia, gelatin, mannitol, starch paster, magnesium trisilicate, talc, corn starch, keratin, paraffin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in a pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the diseases.
The active ingredient may be compounded into, for example, preparations for oral application, preparations for injection, preparations for external application, preparations for inhalation, preparations for application to mucous membranes.
The effective ingredient may usually be administered with a unit dose of 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight, and conditions of the patient or the administering method.
The compound (I) of the present invention has much advantage, such as more selective PGI2 antagonitic activity, stronger activity, more suitable half-life, decreased adverse effect, or the like, compared to the known heterocyclic compounds having the PGI2 antagonitic activity.
The patents, patent applications and publications cited herein above are incorporated by reference.
Abbreviations used in this application are as follows: